June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Omidenepag isopropyl, a selective EP2 agonist, shows additive intraocular pressure (IOP)-lowering effects when used concomitantly with existing anti-glaucoma drugs in animal models
Author Affiliations & Notes
  • Takazumi Taniguchi
    Santen Pharmaceutical Co., Ltd., Ikoma, Japan
  • Tomoko Kirihara
    Santen Pharmaceutical Co., Ltd., Osaka, Japan
  • Miki Takahashi
    Santen Pharmaceutical Co., Ltd., Ikoma, Japan
  • Ryo Iwamura
    Ube Industries, Ltd., Ube, Japan
  • Kenji Yoneda
    Ube Industries, Ltd., Ube, Japan
  • Noriko Odani
    Santen Pharmaceutical Co., Ltd., Osaka, Japan
  • Atsushi Shimazaki
    Santen Pharmaceutical Co., Ltd., Osaka, Japan
  • Masaki Ichikawa
    Santen Pharmaceutical Co., Ltd., Ikoma, Japan
  • Jin-Zhong Zhang
    Santen Inc., Emeryville, California, United States
  • Footnotes
    Commercial Relationships   Takazumi Taniguchi, Santen Pharmaceutical Co., Ltd. (E); Tomoko Kirihara, Santen Pharmaceutical Co., Ltd. (E); Miki Takahashi, Santen Pharmaceutical Co., Ltd. (E); Ryo Iwamura, Ube Industries, Ltd. (E); Kenji Yoneda, Ube Industries, Ltd. (E); Noriko Odani, Santen Pharmaceutical Co., Ltd. (E); Atsushi Shimazaki, Santen Pharmaceutical Co., Ltd. (E); Masaki Ichikawa, Santen Pharmaceutical Co., Ltd. (E); Jin-Zhong Zhang, Santen Inc. (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2105. doi:
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      Takazumi Taniguchi, Tomoko Kirihara, Miki Takahashi, Ryo Iwamura, Kenji Yoneda, Noriko Odani, Atsushi Shimazaki, Masaki Ichikawa, Jin-Zhong Zhang; Omidenepag isopropyl, a selective EP2 agonist, shows additive intraocular pressure (IOP)-lowering effects when used concomitantly with existing anti-glaucoma drugs in animal models. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2105.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Omidenepag isopropyl (OMDI) is a prodrug of omidenepag (OMD), human EP2 receptor agonist with non-prostaglandin structure. Its IOP-lowering effect has been demonstrated in animal models and clinical trials for glaucoma. Here we comprehensively analyzed the receptor binding affinity of OMD, a hydrolyzed form of OMDI, and evaluated additional IOP-lowering effects of OMDI when combining it with existing anti-glaucoma drugs in animal models.

Methods : Binding affinities of OMD to prostanoid receptors (DP1, EP1-4, FP and IP) were determined using recombinantly expressed human receptors. The binding activities of OMD to various non-prostanoid receptors (over 100 molecules) were evaluated by calculating inhibition constants. Agonist activity was evaluated for receptors showing strong binding affinity. Ocular hypotensive effects after single topical administration of OMDI (0.001% in rabbit or 0.0006% in monkey) in combination with 0.5% timolol maleate, 0.15% brimonidine tartrate, or 1% brinzolamide were compared with those of monotherapy in ocular normotensive animals. IOP was measured before, and 2, 4 and 6 hrs after the application of each drug(s).

Results : OMD was a highly EP2 receptor-selective compound, exhibiting a strong binding affinity (Ki=3.6 nM) for its receptor with agonist activity (EC50=8.3 nM). When OMDI was used concomitantly with timolol in rabbits, additional IOP-lowering effect was observed throughout the day compared with monotherapy, and with significant difference (p value<0.01) at 6 hrs after drug application. In monkeys, IOP reduction was also greater in OMDI and brimonidine combination compared to monotherapy throughout the day, with significant difference (p value<0.05) at 2 hrs post-administration. The IOP-lowering effect of co-treatment with OMDI plus brinzolamide was numerically greater compared to either drug alone.

Conclusions : OMD has remarkable selectivity for human EP2, suggesting that OMDI acts through this receptor to lower IOP. Our animal studies suggest that OMDI could be useful in new glaucoma treatments, both as monotherapy as well as combined with existing drugs.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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